Phenyl, (2-pyridyl)propane derivatives



States Patent 055cc Patented Aug. 4, 1959 2,898,338 1 I PHENYL, (Z-PYREYDPROPANE DERIVATIVES Frank J. Villani, Cedar Grove, N.J., assignor to Schering Corporation, Bloomfield, N..I., a corporation of New Jersey No Drawing. Application June 22, 1954 Serial No. 438,636

'5 Claims. (Cl. 260-290) This invention relates to a new group of compounds and to processes for their manufacture. More particularly, this invention relates to a new group of substituted phenyl-(Z-pyridyl)-propanes and their derivatives which are intermediates in the preparation of the therapeutically active propylamine type antihistamines. The compounds of this invention are of the following general formula:

l CH CHzR wherein R represents hydrogen, chlorine, bromine, lower alkyl or lower alkoxy, and R represents amino, chlorine, bromine, hydroxyl, lower alkoxy or benzyloxy.

It is well-known in the art .that the propylamine type antihistamines show a high degree of therapeutic usefulness. 3-phenyl-3-(2-pyridyl) 1 dimethylaminopropane and 3-(p-chlorophenyl) -3- 2-pyridyl) -dimethylaminopropane, typical examples of propylamine-type substances, have found wide clinical application in the treatment of various allergic disorders.

I have now found a new series of transformations which conveniently and economically yield these active antihistaminic substances. Thus, the compounds of this invention provide a novel and useful route by which these therapeutically active substances may be produced.

The compounds of our invention may beprepared by a variety of synthetic schemes depending upon the starting material. For example, in order to prepare a compound of general Formula I wherein R is ethoxy, the following scheme has been applied:

A101 CzHsOCHzCHzCO C1 N Li From the reaction of benzene with B-ethoxypropionyl chloride in the presence of aluminum chloride, the intermediate p-ethoxypropiophenone II is obtained. Further reaction of II with Z-pyridyllithium, according to well-described procedures, yields 1-phenyl1-(2-pyridyl)- 5 3-ethoxypropanol III. Replacement of the tertiary hydroxyl group in III can be efiected in several ways. I prefer to treat the compound with thionyl chloride and subject the halide so formed to the reductive action of zinc in acetic acid, whereupon the ethoxy compound IV is obtained. Alternatively compound IV may be prepared by the reaction of a 2-benzylpyridine with bromoethyl ether in the presence of a basic catalyst as shown below:

NaNH +BICHgCH2OCzH5 I IV+HBr O .HBr O H OHzBr Converting compound V to .an active antihistaminic substance is easily efiected by treating the halide with a suitable amine, such as dimethylamine, whereupon 3- phenyl-3-(2-pyridyl) 1 dimethylaminopnopane is obtained. Alternatively, the halide V can be caused to react with ammonia and the primary amine so obtained may be alkylated as desired in a variety of ways. For example, treating 1-bromo-3-(2-pyridyl) 3 (p-chlorophenyDpropane with liquid ammonia yields (usually under pressure), after removal of the solvent, compound VII, which is one of the group of compounds of my invention. Alkylation of VII with formic acid and formaldehyde yields'the active antihistaminic substance VIII:

flit N CHzOHzBI' H H N I ECHO OHzCHgNHg C H9 0 H3 CHzN CH3 VII VIII Compounds of general Formula I wherein R is amino may alternatively be prepared according to the following equations:

CHQCN Treating a 2-benzylpyridine with chloroacetonitrile yields the intermediate phenyl-Z-pyridylpnopionitrile which, upon reduction, affords the amino compound of general Formula I.

I have also prepared the amino compound from the intermediate fl-phenyl-B-(Z-pyridyl)propionaldehyde by reductive alkylation as shown below:

CHgCHO CHgCHgNHg The compounds of the invention are easily transformed into active therapeutic agents by procedures described in the literature for analogous substances. The members of the group comprising R are easily interconvertible without undue ditficulty. Forexample, thealkoxy compounds are easily cleaved to yield the free hydroxyl compound or the halogen-containing substance, dependent upon the conditions of the reaction. The halogenated compounds may be transformed into the amino compounds by reaction with ammonia as described above. Methylation of the amino compound in any of several ways known to those skilled in the art, such as the use of formic acid and formaldehyde, dimethylsulfate, etc., affords the corresponding dimethylaminopropane, such as 3-phenyl-3-(2-pyridyl)-dimethylaminopropane, which has found wide utility as an antihistaminic agent.

Furthermore, the hydroxy or alkoxy compounds of general Formula I may be dehydrated to yield an intermediate vinyl compound (IX) which, upon reaction with ammonia or an alkylated amine, yields the amino compound of Formula I or the active substance itself as shown below:

Jail

CHzGHgOH H CHg 4 and the residue distilled to yield the ethyl ether of this example, B.P. 148151 C./0.5-1 mm.

EXAMPLE 2 3-(p-chlorophenyl)-3-(Z-pyridyl)-1-br0m0propane hydroli'romide A solution of 0.1 mole of the compound of Example 1 in 350 m1. of 48% hydrobromic acid is refluxed for 24 hours. Upon concentration of the solution in vacuo there is obtained the hygroscopic hydrobromide.

EXAMPLE 3 3-(p-methoxyphenyl) -3-(2-pyridyl) propylamine ammonia and subjected to hydrogenation at 60 under three atmospheres of hydrogen in the presence of Raney nickel catalyst. After removal of the catalyst by filtration, the solvent is distilled in vacuo and the residue fractionated to yield the amine of this example, B.P. 160-164 C./1 mm.

EXAMPLE 4 3- (p-methylphenyl) -3- (2-pyridyl) propylamine The intermediate B-p-methylphenyl-fl-(2-pyridyl)propionitrile is prepared from p-methyl-2-benzylpyridine and chloroacetonitrile according to the procedure of Example 1, B.P. 168-172 C./175 mm.

Hydrogenation of the nitrile obtained above with Raney nickel catalyst according to the procedure of Ex- 7 ample 3, there is obtained the substituted propylamine of this example, B.P. 148150 C./1 mm.

' EXAMPLE 5 3-phenyl-3-(2-pyridyl)pr0pylamine To a solution of 0.1 mole of potassium amide in 500 ml. of liquid ammonia there is added dropwise 0.1 mole of 2-benzylpyridine. After stirring for 10 minutes there is then added 0.1 mole of chloroacetaldehyde diethylmetal and the ammonia solvent is allowed to evaporate. The residual mixture is treated with 160 g. of 30% sulfuric acid in an atmosphere of carbon dioxide for 15 minutes. The mixture is then extracted with ether and the ether solvent is dried with anhydrous sodium sulfate. Upon removal of the ether in vacuo there is obtained the crude intermediate aldehyde which is dissolved in 200 ml. of absolute ethanol. The alcoholic solution of the aldehyde is then saturated with anhydrous ammonia gas and hydrogenated at room temperature under 60 lbs. pressure of hydrogen in the presence of Raney nickel to yield the primary amine of this example, B.P. 130-135 C./ 2 mm.

Alternatively, the amino compound of this example may be prepared in the following manner. A mixture of 7 30 g. of 3-phenyl-3-(2-pyridyl) propanol (see Example 8) and 150 g. of 8% sulfuric acid is heated on a steam bath for 6 hours. After cooling, the mixture is poured on to ice and is neutralized by the careful addition of solid sodium carbonate. The mixture is then extracted with benzene and; after removal of the benzene solvent, the residue is distilled to yield the intermediate 3-phenyl- 3-(2-pyridyl)pr0pylene, B.P. 137140 C./2.5 mm.

Twenty grams of the propylene compound in grams of anhydrous liquid ammonia are heated in a steel autoclave for 15 hours at a temperature of C. After cooling the autoclave is opened and the ammonia allowed to evaporate. Distillation of the residue yields the primary amine ofthis example.

5 EXAMPLE 6 3-p-bromophenyl-3-(2-pyridyl)propylamine The intermediate fi-p-bromophenyl-B-(Z-pyridyl)propionitrile is prepared from p-bromobenzylpyridine and chloroacetonitrile according to the procedure of Example 1. A solution of 0.1 mole of the intermediate nitrile in anhydrous ether is dropwise added to an ether solution of 0.1 mole of lithium aluminum hydride. The reaction mixture is refluxed for 6 hours, decomposed with water, filtered, and the filtrate concentrated in vacuo, whereupon the residue is distilled to yield the primary amine of this example, B.P. 160-163 C./1 mm.

EXAMPLE 7 3-p-chlor0phenyl-3- (2-pyridyl) propanol A mixture of 102 g. of p-chloro-2-benzylpyridine and 55 g. of ethyl bromide in a solution of 150 ml. of anhydrous ether and 150 ml. of anhydrous benzene is added to a stirred suspension of 24 g. of magnesium turnings and 200 ml. of anhydrous ether. The mixture is refluxed for 5 hours whereupon it is cooled to 5 and 44 g. of ethylene oxide is bubbled in while maintaining the low temperature. After allowing the reaction mixture to stand overnight at room temperature, the reaction complex is decomposed with dilute ammonium chloride solution and the organic layer is separated and distilled. The above-entitled propanol is obtained as a pale yellow oil, B.P. 184-190 C./3 mm.

EXAMPLE 8 3-phenyl-3-(Z-pyridyDpropanol From the reaction of Z-benzylpyridine and ethylene oxide, according to the procedure described in Example 7, there is obtained 3-phenyl-3-(2-pyridyl)-propanol, B.P. 164-169 C./1 mm.

EXAMPLE 9 3-phenyl-3- (Z-pyridyl) -1-brom0propane A solution of 1.0 mole of the alcohol obtained in Example 8 in anhydrous benzene containing 1.0 mole of pyridine is cooled in an ice bath while a slight excess of phosphorus tribromide dissolved in anhydrous benzene is slowly added. The resultant mixture is held at 10 C. for three hours, whereupon the solvents are removed in vacuo and the residue is treated with sodium bicarbonate solution and extracted with benzene. The benzene is removed in vacuo yielding the bromo compound of this example, which is of sufiicient purity for further transformation.

The bromide in this example is transformed into the amine of Example 5 in the following manner. By dissolving the bromide in anhydrous dioxane and subjecting 6 the solution to the action of excess anhydrous ammonia in a steel autoclave at C. for 8 hours followed by removal of the solvents in vacuo and distillation of the residue, there is obtained the amine of Example 5.

EXAMPLE 10 3-phenyl-3- (Z-pyridyl) -1-benzyloxypr0pane 4. The compound, 2-(1-phenylpropaue-3-ol)pyridine whose structural formula is:

GHZOH 5. Compounds of the general formula R l i CHzCHzR;

wherein R is a member of the group consisting of hydrogen, chlorine, bromine, lower alkyl and lower alkoxy and R is a member of the group consisting of chlorine, bromine and hydroxyl.

References Cited in the file of this patent UNITED STATES PATENTS 2,656,358 Sperber Oct. 20, 1953 2,667,491 Sutherland Jan. 26, 1954 2,676,964 Sperber Apr. 27, 1954 2,694,706 Cusic Nov. 16, 1954 

5. COMPOUNDS OF THE GENERAL FORMULA 